FDA Warning – AMAG Pharmaceuticals, Inc.

TRANSMITTED BY FACSIMILE

Brian J.G. Pereira, MD
President and Chief Executive Officer
AMAG Pharmaceuticals, Inc.
100 Hayden Avenue
Lexington, MA 02421
RE: NDA 020410, 022180
GastroMARK® (ferumoxsil, oral suspension)
Feraheme™ (ferumoxytol) Injection For Intravenous (IV) use
MACMIS #18355

WARNING LETTER

Dear Dr. Pereira:
As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed AMAG Pharmaceuticals, Inc.’s (AMAG) webpages for its drug products, GastroMARK® (ferumoxsil, oral suspension) (GastroMARK)1 and Feraheme™ (ferumoxytol) Injection For Intravenous (IV) use (Feraheme).2 Both the GastroMARK and Feraheme webpages omit risks associated with the drug products; in addition, the GastroMARK webpage omits important information about the approved indication for GastroMARK, and both webpages misleadingly suggest unapproved new uses for the drugs. Thus, the webpages misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a),(f)(1) & (n); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1); 201.128; 202.1(e)(3)(i);(e)(5) & (e)(6)(i). Furthermore, AMAG failed to submit a copy of the GastroMARK and Feraheme webpages to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).
These violations are concerning from a public health perspective because they suggest that GastroMARK is useful in a broader range of patients and conditions than has been demonstrated by substantial evidence or substantial clinical experience, and that GastroMARK and Feraheme are safer than has been demonstrated by substantial evidence or substantial clinical experience.

Background
GastroMARK
According to its FDA-approved product labeling (PI), GastroMARK is indicated as follows:
GastroMARK is indicated in adult patients for oral use with magnetic resonance imaging to enhance the delineation of the bowel to distinguish it from organs and tissues that are adjacent to the upper regions of the gastrointestinal tract.
GastroMARK’s usefulness in the lower gastrointestinal tract and retroperitoneal region is limited (by transit time and dilution).
GastroMARK is not recommended for iron supplementation.
GastroMARK is contraindicated in patients with known or suspected intestinal perforation or obstruction, and in patients with known allergy to its active or inactive ingredients.
The PI for GastroMARK includes the following Warnings:
The ingestion of GastroMARK may cause abdominal pain, diarrhea, nausea and vomiting. In 78/256 (30%) of patients and normal volunteers, gastrointestinal adverse events occurred within the first 2 hours after ingestion of GastroMARK. In 30 (12%), gastrointestinal events had their onset within 30 minutes. In 63/256 (24%), diarrhea occurred within 24 hours.
Vomiting can be associated with aspiration. Precautions should be taken to avoid aspiration.
The effects of GastroMARK on human peritoneal tissues are not known. In animal studies, intraperitoneal injection of GastroMARK was associated with a foreign body reaction that persisted for at least 30 days.
Additionally, the PI contains numerous Precautions, including the possibility of increased severity of nausea, vomiting, diarrhea, and abdominal cramping in patients who have these symptoms prior to GastroMARK administration; “This could confound the ability to distinguish adverse effects of GastroMARK from the signs and symptoms of obstruction or perforation, and from the pre-existing conditions.” In addition, studies have not been conducted in patients who have a current or recent history of hiatal hernia, esophageal reflux, nausea, vomiting, or abdominal pain; or to describe the effects of drugs that increase or decrease gastrointestinal transit time on the GastroMARK image quality or gastrointestinal adverse events. GastroMARK should be given with caution to patients who cannot tolerate large fluid shifts, who are on specific fluid intake requirements, and who have disorders associated with iron overload (e.g., hemosiderosis, chronic hemolytic anemia with frequent blood transfusions, or chronic iron replacement). Furthermore, the safety of GastroMARK in patients with inflammatory bowel disease has not been well studied.
Feraheme
According to its PI, “Feraheme™ (ferumoxytol) Injection is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).”
Feraheme is contraindicated in patients with evidence of iron overload, known hypersensitivity to Feraheme or any of its components, and anemia not caused by iron deficiency.
Feraheme is associated with other serious risks. The PI includes Warnings and Precautions regarding the following (emphasis in original):
. . . HYPERSENSITIVITY REACTIONS
Feraheme may cause serious hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. In clinical studies, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. Observe patients for signs and symptoms of hypersensitivity for at least 30 minutes following Feraheme injection and only administer the drug when personnel and therapies are readily available for the treatment of hypersensitivity reactions. . . .
. . . HYPOTENSION
Hypotension may follow Feraheme administration. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Monitor patients for signs and symptoms of hypotension following Feraheme administration. . . .
. . . IRON OVERLOAD
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy. . .

In the 24 hours following administration of Feraheme, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Feraheme complex.
. . . MAGNETIC RESONANCE (MR) IMAGING
Administration of Feraheme may transiently affect the diagnostic ability of MR imaging
. . . . Alteration of MR imaging studies may persist for up to 3 months following the last Feraheme dose. . . .
Feraheme will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission tomography (SPECT), ultrasound or nuclear medicine imaging.

The most common adverse reactions reported in ≥2% of Feraheme-treated patients with CKD were nausea (3.1%), dizziness (2.6%), hypotension (2.5%), and peripheral edema (2.0%). Diarrhea (4.0%), constipation (2.1%), and hypertension (1.0%) have also been reported. In clinical trials, adverse reactions leading to treatment discontinuation in ≥2 Feraheme-treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
Omission of Risk/Indication Information
Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials.
The webpages present numerous efficacy claims for GastroMARK and Feraheme, but fail to communicate any of the risks associated with the drugs (see Background section above). By omitting the most serious and frequently occurring risks associated with these drugs, the webpages misleadingly suggest that GastroMARK and Feraheme are safer than has been demonstrated and therefore place the public at risk. For example, the GastroMARK webpage omits the drug’s contraindication in patients with known or suspected intestinal perforation or obstruction. We note that there are links to “Download the GastroMARK® Package Insert” at the bottom of the GastroMARK webpage and to “Download the Feraheme Package Insert” buried in the second sentence of the Feraheme webpage. However, these links do not mitigate the complete omission of risk information from the GastroMARK and Feraheme webpages.
Furthermore, the GastroMARK webpage fails to present the complete indication for GastroMARK, including material limitations to the indication. The webpage includes the following claims:
GastroMARK® (ferumoxsil) is AMAG Pharmaceuticals’ oral gastrointestinal (GI) imaging agent for delineation of the bowel. . . . By more clearly identifying the intestinal loops, GastroMARK® enhances the ability to distinguish the bowel from adjacent tissues and organs in the upper gastrointestinal tract.
This presentation fails to include that GastroMARK is indicated only in adult patients, and that its usefulness in the lower gastrointestinal tract and retroperitoneal region is limited by transit time and dilution. The webpage also fails to reveal that GastroMARK is not recommended for iron supplementation.
Promotion of Unapproved Uses
The Feraheme webpage includes the following claims:
• “Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease.”
• “Feraheme is being developed to treat iron deficiency anemia associated with other conditions and disease states including women with abnormal uterine bleeding, and patients with cancer and gastrointestinal diseases.”
• “Feraheme is also being developed as a diagnostic agent for vascular-enhanced magnetic resonance imaging to assess peripheral arterial disease. . . .”
The presentation of both approved and unapproved product information for Feraheme together in this manner is misleading because it implies that Feraheme is effective for unapproved uses. However, Feraheme is not approved to treat iron deficiency anemia in women with abnormal uterine bleeding, or in patients with cancer and gastrointestinal diseases. In addition, Feraheme is not approved as a diagnostic agent for vascular-enhanced magnetic resonance imaging for the detection of clinically significant arterial stenosis or occlusion in subjects with peripheral arterial disease.
Similarly, the GastroMARK webpage first presents the product’s U.S. indication (minus limitations), along with efficacy claims for the drug, but states near the bottom of the page that, “In Europe Gastromark® is approved for rectal administration to delineate the lower intestinal system” (emphasis added). This statement, presented within a webpage that appears to be targeted to a U.S. audience, is concerning, as it suggests to U.S. healthcare professionals that GastroMARK is effective for delineating the lower intestinal system and for rectal administration, when in fact, the drug is not approved for this use or method of administration in the U.S.; the U.S. PI for GastroMARK specifically states that “GastroMARK is indicated. . . for oral use. . . .” and that “GastroMARK’s usefulness in the lower gastrointestinal tract and retroperitoneal region is limited (by transit time and dilution).”
The above statements thus misbrand Feraheme and GastroMARK.
Failure to Submit on Form FDA-2253
FDA regulations require companies to submit any labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current professional labeling. Copies of the GastroMARK and Feraheme webpages were not submitted to DDMAC under cover of Form FDA-2253 at the time of initial publication as required by 21 CFR 314.81(b)(3)(i).
Conclusion and Requested Action
For the reasons discussed above, the webpages misbrand GastroMARK and Feraheme in violation of the Act, 21 U.S.C. 352(a),(f)(1) & (n); 321(n), and FDA’s implementing regulations. See 21 CFR 201.100(c)(1); 201.128; 202.1(e)(3)(i);(e)(5) & (e)(6)(i). Furthermore, you failed to submit the webpages to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).
DDMAC requests that AMAG immediately cease the dissemination of violative promotional materials for GastroMARK and Feraheme, such as those described above. Please submit a written response to this letter on or before November 1, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for GastroMARK and Feraheme that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18355 in addition to the NDA numbers. We remind you that only written communications are considered official.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for GastroMARK and Feraheme comply with each applicable requirement of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.
Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, R.Ph., M.B.A.
Director
Division of Drug Marketing,
Advertising, and Communications
CC: Russell D. Reed
Global Labeling Director
Mallinckrodt Inc.
675 McDonnell Boulevard
Hazelwood, MO 63042

1 GastroMARK webpage, at http://www.amagpharma.com/products/gastromark.php (last accessed October 18, 2010).
2 Feraheme webpage, at http://www.amagpharma.com/products/feraheme.php (last accessed October 18, 2010).
———————————————————————————————————
This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
—————————————————-
THOMAS W ABRAMS
10/18/2010

FDA Issued Warning – Nobel Laboratories, LLC

October 21, 2010
2011-DAL-WL-001
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Fasprin Health, LLC / Nobel Laboratories, LLC
Attn: Edward J. Petrus, MD
President, Fasprin Health, LLC / Nobel Laboratories, LLC
3413 Spanish Oak Dr.
Austin, TX 78731

Dear Dr. Petrus:

This letter concerns “FASPRIN®” (Fasprin), which is marketed by your firm in quick dissolving tablet form as an over-the-counter (OTC) internal analgesic product. According to the package labeling, Fasprin is used for temporary relief of occasional headaches, minor aches and pains and for relief of fever (internal analgesic and antipyretic uses), as well as for various other uses. Fasprin’s package label identifies aspirin as the active ingredient and each tablet contains 81 mg of aspirin. Other labeling identifies glucosamine, zinc salt and magnesium salt as active ingredients for other drug uses, as described below.

The labeling for Fasprin contains statements that cause the product to be a drug, as defined by section 201 (g) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321 (g)).

The following are examples of intended drug uses described in the labeling for this product:

From the package label

• “Purpose[:] Pain Reliever/Fever Reducer”
• ”The Easy Way to Maintain Your Daily Aspirin Regimen” directly above a vignette of an EKG and a heart
• “Clinical Studies Indicate Low-Dose Aspirin Therapy Helps Reduce The Risk Of Heart Attack Or Stroke”
• “Daily Use Of Low-Dose Aspirin is Recommended By The American Heart Association”
• “Take FASPRIN For Emergency Treatment. At First Signs Of Heart Attack Or Stroke Call 911, Take Two FASPRIN ….”

Additional labeling claims from your websites,
(http://www.nobellabs.com/pages/fasprin.htmlhttp://www.fasprin.com and
http://www.fasprinhealth.com). and product brochure (available athttp://www.fasprin.com/)
• “ideal for: Daily low dosage aspirin therapy
Usage at the onset of symptoms of stroke …
Arthritis pain treatment.”
• “with regular use … reduces blood pressure and enhances blood flow in small vessels”
• “Additionally the FDA advises physicians to prescribe aspirin for patients with angina (chest pain), to reduce the risk of death in patients with a suspected acute heart attack, to prevent recurrent heart attacks, prevent stroke (blockage of blood flow to the brain), and treat transient ischemic attacks (mini-stroke)”
• “Every other day use of aspirin had a 44% reduction in the incidence of first myocardial infarction”
• After describing the process of a heart attack the website states “aspirin should be given within 1 hour of the start of heart attack symptoms.”
• “Fasprin also contains glucosamine to protect the lining of the mouth and GI tract; a zinc salt to promote healing of any ulcerationsplus to help prevent tinnitus associated with salicylates, and a magnesium salt to buffer the aspirin and decrease acid production in the stomach.”
• “Fasprin® incorporates glucosamine and a zinc salt to prevent any irritation.”
• “Figures show that long-term use of aspirin may double the chance of living a healthy life into your 90s!”
• “Low dose aspirin can reduce the risk [of Deep Vein Thrombosis] by 36 percent”
• “Did you know that the daily use of aspirin • Reduces the risk of stroke by 30% • Reduces the risk of Alzheimer’s disease by 50% • Reduces the risk of Parkinson’s disease by 45%”
• “Aspirin use is linked to lower rates of cancer”
• “Low dose aspirin reduces the risk of colon cancer by 50-60%”
• “Aspirin use treats and prevents periodontal disease”
• “Aspirin use reduced vision loss in elderly”
• “Aspirin prevents gall stone formation”
• “Aspirin may improve cognitive function in Alzheimer’s patients”

As labeled, Fasprin is a drug under section 201(g)(1)(B) of the Act (21 U.S.C. § 321 (g)(1)(B)), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man (e.g., cardiovascular-related diseases, arthritis, colon cancer, Alzheimer’s disease, Parkinson’s disease, gall stone formation, vision loss, periodontal disease, and longevity), and under section 201(g)(1)(C) of the Act (21 U.S.C. § 321 (g)(1)(C)), because it is intended to affect the structure or function of the body.

New Drug Violation

A. New indications for use, combination of active ingredients and dosage

Based on the combination of active ingredients and claims made for this product, Fasprin is a “new drug” within the meaning of section 201(p) of the Act (21 U.S.C. § 321(p)). Although the “Purpose” section of Fasprin’s Drug Facts panel states that Fasprin is intended as a “Pain Reliever/Fever Reducer,1Fasprin’s labeling claims demonstrate that one of its primary marketed intended uses is for cardiovascular-related diseases and events, including heart attacks, strokes and deep vein thrombosis. As described in 21 C.F.R. § 343.80, certain claims for the
treatment or prevention of cardiovascular- and cerebrovascular-related diseases are permissible only in professional labeling for aspirin. According to the labeling, Fasprin is also intended for arthritis pain treatment; reducing the risk of Alzheimer’s, Parkinson’s disease and colon cancer; treating and preventing periodontal disease, reducing vision loss; preventing gall stone formation; and increasing longevity. Fasprin’s uses for Alzheimer’s disease, Parkinson’s disease, colon cancer, periodontal disease, vision loss, gall stone formation, arthritis pain relief, and longevity are not covered by the tentative final monograph (TFM) for OTC internal analgesics (53 Fed. Reg. 46204, Nov. 16, 1988) or the final rule covering professional labeling for internal analgesics (63 Fed. Reg. 56802, Oct. 23, 1998). Moreover, we are not aware of evidence to show that Fasprin, as formulated and labeled, is generally recognized as safe and effective.

In addition, several of the above claims discuss Fasprin containing glucosamine, a zinc salt, and “a magnesium salt” intended for uses that represent and suggest they are active ingredients under 21 C.F.R. § 201.66(b)(2), based on the claims they are components intended to furnish pharmacological activity or other direct effect in the mitigation or treatment of disease or to affect the function of the body.2 The Internal Analgesics TFM did not include the combination of aspirin, glucosamine, zinc salt, and “a magnesium salt” as a combination of active ingredients, nor was this combination of ingredients evaluated as part of the Food and Drug Administration’s (FDA’s) OTC Drug Review for any of the internal analgesic/pain relief uses found in the labeling for Fasprin.

Also, the labeled directions for adult analgesic use of Fasprin specify a 81 mg daily dosage of “1 tablet daily” which falls within the range of the dosage listed in the professional labeling for aspirin for cardiovascular-related indications (see 21 C.F.R. § 343.80), but is well below the dosages for pain and fever relief that were’ considered in the Internal Analgesics TFM and OTC Drug Review. See 53 Fed. Reg. 46204 at 46257.

Therefore, based on the combination of active drug ingredients, dosage, and its labeled uses in mitigating, treating or preventing cardiovascular- and cerebrovascular-related diseases, Alzheimer’s disease, Parkinson’s disease, colon cancer, periodontal disease, vision loss, gall stone formation, arthritis pain relief, and longevity, as described above, Fasprin is a “new drug” within the meaning of section 201 (p) of the Act (21 U.S.C. § 321 (p)), as further described in 21 C.F.R. § 310.3(h), because it is not generally recognized as safe and effective for such labeled uses. Fasprin is not covered by FDA’s OTC Drug Review because no product formulated with this combination of active ingredients and dosage, and labeled for these intended uses has previously been commercially marketed on or before the inception of that review, and the Agency has never proposed that such a product be included in that Review. Thus, the current marketing of Fasprin violates section 505(a) of the Act (21 U.S.C. § 355(a)), because it is a “new drug” and it is not the subject of an approved new drug application.

B. New dosage form and method of administration

In addition, Fasprin for the uses described above is in a dosage form that is not generally recognized as safe and effective. According to its package labeling, Fasprin is a tablet that “Dissolves In Your Mouth Not In Your Stomach[,]” is ” • Fast Acting” and is ” • Quick Dissolv[ing].” According to its websites (http://www.nobellabs.com/pages/fasprin.html andhttp://www.fasprin.com), Fasprin “melts in the mouth after contact with saliva on the tongue and is absorbed by the lining of the mouth, avoiding first-pass metabolism” and “Get[s] into the blood stream faster,” such that, “[t]he protective action of aspirin is available within 5 minutes after absorption in the mouth.” Fasprin’s website “Q&A” goes on to explain “[s]ince Fasprin is absorbed by the lining of the mouth and carried with about 140 blood vessels, no tablet makes contact with the lining of the stomach to cause direct irritation.”

FDA is not aware of any evidence demonstrating that a fast acting quick dissolve internal analgesic tablet absorbed by the lining of the mouth was marketed at the inception of or considered under the OTC Drug Review. Because the dosage form is intended to avoid first-pass metabolism and be absorbed by the lining of the mouth unlike the dosage form covered by the Internal Analgesics TFM, without review of safety and efficacy data, the agency cannot conclude that such a dosage form is suitable for dosing conditions established under that TFM. A product that is initially marketed after the inception of the OTC Drug Review and that does not fully meet conditions established under the procedural regulation established in the OTC Drug Review is ineligible for the OTC Drug Review and requires an FDA-approved drug application before it can be legally marketed in the U.S. 21 C.F.R. §§ 330.1, and 330.10(b); 21 U.S.C. §§ 321(p) and 355(a).

As a result, Fasprin’s dosage form and method of administration are not generally recognized as safe and effective. 21 C.F.R. §§ 330.1, and 330.10(b). Therefore, Fasprin is a “new drug,” as defined in section 201(p) of the Act (21 U.S.C. § 321 (p)). See also 21 C.F.R. § 310.3(h)(5). The current marketing of Fasprin in the United States violates section 505(a) of the Act (21 U.S.C. § 355(a)), because it is a “new drug” and it is not the subject of an approved new drug application.

Misbranding Violations

Furthermore, Fasprin is misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)) because it does not bear adequate directions for its intended cardiovascular and arthritis use. “Adequate directions for use” is defined in 21 C.F.R. § 201.5 as “directions under which the layman can use a drug safely and for the purposes for which it is intended.” Thus, if an indication requires the supervision of a practitioner licensed to prescribe drugs, adequate directions for use cannot be written for consumer directed OTC use. See U.S. v Articles of Drug, 625 F.2d 665, 672-673 (5th Cir. 1980). The directions are also inadequate under 21 C.F.R. §201.5 because the label does not include a “Uses” section as required by 21 C.F.R. § 201.66(c)(4) to identify the intended uses. In addition, Fasprin’s direction to take one 81 mg tablet daily is inadequate with respect to the aspirin doses considered under the OTC Drug Review for pain and fever relief and thus it is misbranded under 502(f)(1).

Fasprin is also misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)) because the labeling of Fasprin as “The Easy Way to Maintain Your Daily Aspirin Regimen” is misleading when juxtaposed with the ten and three day limitations for pain and fever use, respectively, as set forth under the “Do Not Use” section and with the “take 1 to 4 tablets and repeat hourly, not to exceed 20 tablets during a 24 hour period” included on Fasprin’s website. The statements on the labeling send consumers a mixed message about the purpose of the product and the duration for which it can be safely used and as such the labeling is misleading. Additionally, because these labeled warnings are undermined by the inconsistent and incompatible language pertaining to the use as a daily regime with no time frame, Fasprin fails to bear adequate warnings against unsafe duration of administration and, therefore, is also misbranded under section 502(f)(2) of the Act (21 U.S.C. § 352(f)(2)).

Fasprin is also misbranded under 502(a) and 502(f)(2) because its immediate container, which is the blister card, does not contain the Reyes Syndrome warning as required for aspirin containing internal analgesic products under 21 C.F.R. § 201.314(h).

As previously discussed, Fasprin labeling claims that Fasprin contains glucosamine, a zinc salt, and “a magnesium salt” intended for uses that represent and suggest the ingredients are active ingredients under 21 C.F.R. § 201.66(b)(2). Accordingly, all three ingredients are required to be listed as active ingredients under 21 C.F.R. § 201.10 and 21 U.S.C. § 352(e)(1)(A)(ii). However, Fasprin’s label only lists glucosamine (Glucosamine Sulfate-K) and a zinc salt (Zinc Gluconate) as inactive ingredients and does not list any magnesium salt ingredient. As a result Fasprin is misbranded under 502(a) and 502(e)(1)(A)(ii).

Fasprin is further misbranded under section 502(e)(1)(A)(ii) of the Act (21 U.S.C. § 352(e)(1)(A)(ii)) because it fails to list and declare the quantity of all active ingredients. As previously discussed the glucosamine, zinc salt and “a magnesium salt” contained in Fasprin are active ingredients under 21 C.F.R. § 201.66(b)(2). Also, based on the labeled claims, “a magnesium salt” is present in the formulation, as noted above. However, there are no magnesium-containing ingredients listed on the package labeling. As neither glucosamine, zinc salt nor magnesium salt is listed as an active ingredient of Fasprin, the product is misbranded under section 502(e)(1)(A)(ii) of the Act.

In addition to the above violations, Fasprin is also misbranded under section 502(c) of the Act (21 U.S.C. § 352(c)), because the product is not labeled in accordance with the “Drug Facts” labeling requirements described in 21 C.F.R. § 201.66. For example, there is no “Uses” section under the “Drug Facts” as required by 21 C.F.R § 201.66(c)(4).

Finally, the introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301 (a) of the Act (21 U.S.C. § 331 (a)). Therefore, the marketing of Fasprin in the United States violates this provision of the Act.

The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products, nor are the arguments raised here regarding them exhaustive. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct the referenced violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction.

Please send your reply to the Food and Drug Administration, Attention: Sherrie L. Krolczyk, Compliance Officer at the letterhead address. If you have questions regarding the content of this letter, please contact Sherrie L. Krolczyk at 214-253-5312.

Sincerely,

/S/

Reynaldo R. Rodriguez, Jr.
Dallas District Director
RRR/sik

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1 Aspirin for use as a pain and fever reducing internal analgesic is addressed in the OTC Drug Review under the Tentative Final Monograph (TFM) issued on November 16, 1988 for OTC Internal Analgesics.

2 The specific glucosamine and zinc salt listed on Fasprin’s label are Glucosamine Sulfate-K and Zinc Gluconate, both of which are listed as inactive ingredients. While the labeling also discusses the use of a magnesium salt, there is no magnesium salt listed under either the active ingredient or inactive ingredient headers.